Cancer Management Chapter 30: Chronic myeloid leukemia

March 15, 2010

Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder resulting from the neoplastic transformation of the primitive hematopoietic stem cell. The disease is monoclonal in origin, affecting myeloid, monocytic, erythroid, megakaryocytic, B-cell, and, sometimes, T-cell lineages. Bone marrow stromal cells are not involved.

Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder resulting from the neoplastic transformation of the primitive hematopoietic stem cell. The disease is monoclonal in origin, affecting myeloid, monocytic, erythroid, megakaryocytic, B-cell, and, sometimes, T-cell lineages. Bone marrow stromal cells are not involved.

CML accounts for 15% of all leukemias in adults. Approximately 5,050 new cases of CML will be diagnosed in 2009, and it is estimated that 470 patients will die of CML this year. The incidence is 1.7 per 100,000 population. With imatinib (Gleevec) therapy, the annual mortality has been reduced significantly (less than 2%-3% per year).

Epidemiology

Gender
The male-to-female ratio is 1.1:1 to 1.4:1.

Age
According to SEER and MRC data, the median age of patients with CML is 66 years. However, most patients who are admitted to medical therapy studies are 50 to 60 years old, (median: approximately 53 years). Patients in bone marrow transplantation (BMT) studies are even younger, (median age: approximately 40 years). Age differences must be considered in all studies, because this variable may affect results.

Etiology and risk factors

The etiology of CML is unclear. Some associations with genetic and environmental factors have been reported, but, in most cases, no such factors can be identified.

Genetic factors
There is little evidence linking genetic factors to CML. Offspring of parents with CML do not have a higher incidence of CML than does the general population.

Environmental factors
Nuclear and radiation exposures, including therapeutic radiation, have been associated with the development of CML. Exposure to chemicals has not been consistently associated with greater risk.

Signs and symptoms

CML usually runs a biphasic or triphasic course. This process includes an initial chronic phase and a terminal blastic phase, which is preceded by an accelerated phase in 60% to 80% of patients.

Chronic phase
If untreated, chronic-phase CML is associated with a median survival of 3.5 to 5.0 years. During the chronic phase, CML is asymptomatic in 25% to 60% of all cases; in these cases, the disease is discovered on a routine blood examination.

In symptomatic patients, the most common presenting signs and symptoms are fatigue, left upper quadrant pain or mass, weight loss, and palpable splenomegaly. Occasionally, patients with very high WBC counts may have manifestations of hyperviscosity, including priapism, tinnitus, stupor, visual changes from retinal hemorrhages, and cerebrovascular accidents.

Patients in chronic-phase CML do not have an increased risk for infection. Splenomegaly is documented in 30% to 70% of patients. The liver is enlarged in 10% to 20% of cases.

Accelerated phase
This is an ill-defined transitional phase. The criteria used recently in all the studies with tyrosine

kinase inhibitors include the presence of 15% to 29% blasts, at least 30% blasts and promyelocytes, or at least 20% basophils in the peripheral blood or a platelet count < 100 × 109/L unrelated to therapy. Cytogenetic clonal evolution is also a criterion for acceleration. Other classifications include more subjective criteria (Table 1). The classification used may affect the expected outcome for a group of patients defined as accelerated phase. With imatinib therapy, the estimated 4-year survival rate exceeds 50%.

The accelerated phase is frequently symptomatic, including the development of fever, night sweats, weight loss, and progressive splenomegaly.

Blastic phase
The blastic phase morphologically resembles acute leukemia. Its diagnosis requires the presence of at least 30% of blasts in the bone marrow or peripheral blood. The WHO has proposed to consider blast phase with at least 20% blasts, but this classification has not been validated, and recent evidence suggests that patients with 20% to 29% blasts have a significantly better prognosis than do those having at least 30% blasts. In some patients, the blastic phase is characterized by extramedullary deposits of leukemic cells, most frequently in the CNS, lymph nodes, skin, or bones.

Patients in blastic phase usually die within 3 to 6 months. Approximately 70% of patients in blastic phase have a myeloid phenotype, 25% have a lymphoid phenotype, and 5% have an undifferentiated phenotype. Prognosis is slightly better for a lymphoid blastic phase than for myeloid or undifferentiated cases (median survival: 9 vs 3 months).

Patients in the blastic phase are more likely to experience symptoms, including weight loss, fever, night sweats, and bone pain. Symptoms of anemia, infectious complications, and bleeding are common. Subcutaneous nodules or hemorrhagic tender skin lesions, lymphadenopathy, and signs of CNS leukemia may also occur.

Laboratory features

Peripheral blood
The most common feature of CML is an elevated WBC count, usually exceeding 25 × 109/L and frequently exceeding 100 × 109/L, occasionally with cyclic variations. The finding of unexplained, persistent leukocytosis (eg, > 12-15 × 109/L) in the absence of infections or other causes of WBC count elevation should prompt a work-up for CML.

The WBC differential usually shows granulocytes in all stages of maturation, from blasts to mature, morphologically normal granulocytes. Basophils are elevated, but only 10% to 15% of patients have ≥ 7% basophils in the peripheral blood. Frequently, eosinophils are also mildly increased. The absolute lymphocyte count is elevated at the expense of T lymphocytes.

The platelet count is elevated in 30% to 50% of patients and is higher than 1,000 × 109/L in a small percentage of patients with CML. When thrombocytopenia occurs, it usually signals disease acceleration.

Some patients have mild anemia at diagnosis.

Neutrophil function is usually normal or only mildly impaired, but natural killer (NK) cell activity is impaired. Platelet function is frequently abnormal but usually has no clinical significance.

Bone marrow
The bone marrow is hypercellular, with cellularity of 75% to 90%. The myeloid-to-erythroid ratio is usually 10:1 to 30:1. All stages of maturation of the WBC series are usually seen, but the myelocyte predominates.

Megakaryocytes are increased in number early in the disease and may show dysplastic features. They are usually smaller than the typical normal megakaryocytes. Fibrosis may be evident at diagnosis, but it is more common with disease progression and is usually an adverse prognostic finding.

Other laboratory findings
Leukocyte alkaline phosphatase activity is reduced at diagnosis. Serum levels of vitamin B12 and transcobalamin are increased, sometimes up to 10 times normal values. Serum levels of uric acid and lactic dehydrogenase (LDH) are also frequently elevated.

Cytogenetic and molecular findings

Philadelphia (Ph) chromosome
CML is characterized by the Ph chromosome, which represents a balanced translocation between the long arms of chromosomes 9 and 22, t(9;22)(q34;q11.2). The ABL1 proto-oncogene located in chromosome 9q34 encodes for a nonreceptor protein-tyrosine kinase expressed in most mammalian cells. In chromosome 22, the breakpoint occurs within the BCR gene and usually involves an area known as the major breakpoint cluster region (m-BCR), located either between exons b3 and b4 or between exons b2 and b3. Therefore, two different fusion genes can be formed, both of them joining exon 2 of ABL1 with either exon 2 (b2a2) or exon 3 of BCR (b3a2). Among the 5% to 10% of patients who do not have the Ph chromosome detected by karyotyping, 30% to 40% have the molecular rearrangement identified by fluorescent in situ hybridization (FISH)/polymerase chain reaction (PCR). Those patients without this rearrangement are considered to have “atypical CML,” a unique entity having a different natural history, prognosis, and treatment.

Upon translation, a new protein with a molecular weight of 210 kd (p210BCR-ABL) is synthesized, which, when compared with the normal ABL1, has markedly increased kinase activity and can transform transfected cells and induce leukemia in transgenic mice. Occasionally, the breakpoint can occur in other areas (BCR and μ-BCR), leading to different transcripts (eg, p190BCR-ABL and p230BCR-ABL, respectively). The mechanism of oncogenesis of p210BCR-ABL is unclear, but, upon phosphorylation, it can activate several intracellular pathways, including the Ras and the mitogen-activated protein kinase pathway, the Jak-Stat pathway, the PI3 kinase pathway, and the MYC pathway. Ultimately, this leads to altered adhesion to extracellular matrix and stroma, constitutive activation of mitogenic signals, and inhibition of apoptosis.

Staging and prognosis

Staging systems
Several characteristics of CML affect the prognosis, including age, spleen size, WBC and platelet counts, and percentage of blasts, eosinophils, and basophils in the peripheral blood. Deletions of the derivative chromosome 9 are identified in 10% to 15% of patients and have been associated with an adverse prognosis with most treatment modalities. Imatinib may overcome the adverse prognosis associated with del der(9). These factors have been incorporated into several staging systems.

Sokal's classification
A frequently used risk classification is Sokal's prognostic risk system. In this system, the hazard ratio function is derived from the following formula: λi(+)/λo(t) = Exp 0.0116 (age - 43.4) + 0.0345 (spleen - 7.51) + 0.188 [(platelets/700)2 - 0.563] + 0.0887 (blasts - 2.10).

This risk classification defines three prognostic groups with hazard ratios of < 0.8, 0.8.-1.2, and > 1.2 (ie, low-, intermediate-, and high-risk).

The Hasford classification has been suggested to separate more clearly and without overlap risk groups among patients treated with interferon therapy. The Hasford score is derived from the formula (0.6666 × age [0 when age < 50 years; 1, otherwise] + 0.0420 × spleen size [cm below costal margin] + 0.0584 × blasts [%] + 0.0413 × eosinophils [%] + 0.2039 × basophils [0 when basophils < 3%; 1, otherwise] + 1.0956 × platelet count [0 when platelet count < 1,500 × 109/L; 1, otherwise]) × 1000. Based on the score, patients can be classified into three risk groups: low (score ≤ 780), intermediate (score > 780 and ≤ 1,480), and high (score ≥ 1,480). This classification may be less predictive in the imatinib era.

Treatment

Chronic phase

Conventional chemotherapyBusulfan (Busulfex, Myleran) and hydroxyurea (Hydrea) were the chemotherapeutic agents used most frequently in CML until the development of imatinib. Busulfan is now rarely used.

Hydroxyurea is most frequently used to control the WBC while confirming the diagnosis of CML. The dose can be adjusted individually to control the WBC count. In some instances, a dose of 10 to 12 g/d may be needed.

Neither busulfan nor hydroxyurea significantly reduces the percentage of cells bearing the Ph chromosome, and, therefore, the risk of transformation to the blastic phase is unchanged. Their use should be limited to temporary control of hematologic manifestations before definitive therapy (eg, imatinib, stem-cell transplantation) is instituted. Once the diagnosis of CML is confirmed, imatinib should be initiated immediately. There is usually no need for or benefit to initially “debulking” with hydroxyurea.

Interferon
Interferon-α can induce a complete hematologic response (Table 2) in 70% to 80% of patients with CML, and with some degree of suppression of Ph chromosome-positive cells (ie, cytogenetic response) in 40% to 60% of patients, which is complete in up to 20% to 25% of patients. Randomized studies have documented a survival advantage for patients treated with interferon-α who achieved a major, and particularly a complete, cytogenetic response.

Patients who achieve a complete cytogenetic response have a 10-year survival rate of 75% or more, compared with less than 40% for those having a partial response and less than 30% for individuals having a lesser or no response.

Interferon and cytarabine (Ara-C) The combination of interferon-α and low-dose Ara-C induced a higher (ie, 40%-50%) response rate, and possibly a survival advantage, when compared with interferon-α alone.

Approximately 30% of those achieving complete cytogenetic remission with interferon-α may achieve a sustained molecular remission and are probably cured. Among the others, 40% to 60% remain free of disease after more than 10 years despite the presence of minimal residual disease. This has been called “operational cure.”

Formulations of interferon-α attached to polyethylene glycol (PEG) have a longer half-life that allows for weekly administration and may have decreased toxicity.

Imatinib is a potent inhibitor of the tyrosine kinase activity of bcr-abl and a few other tyrosine kinases, such as PDGF-R (platelet-derived growth factor-receptor) and KIT. It has demonstrated significant activity in patients with CML in all phases of the disease, whether they have received prior therapy or not. Among patients with chronic-phase CML for whom prior interferon-α therapy failed, 55% to 85% of patients achieved a major cytogenetic remission,including 45% to 80% with a complete cytogenetic remission. The estimated rate of survival free of transformation to accelerated with blast phase is 69% at 60 months. Among patients treated in early chronic-phase CML who had not received prior therapy, the rate of complete cytogenetic response is 82%, with an overall survival rate at 84 months of 93%, and event-free survival being 81%.

Overall and event-free survivals with imatinib therapy are significantly better than those seen with other therapies. Thus, imatinib has become the standard therapy for CML (Figure 1). The proper management of patients receiving imatinib is important.

Dose The standard dose of imatinib is 400 mg/d for the chronic phase and 600 mg for the accelerated and blastic phases. Dose reductions may be needed in some patients because of toxicity, but doses less than 300 mg/d are not recommended. Available data from the phase I study show a clear decrease in the probability of response with doses lower than 300 mg/d. Several studies have suggested that starting therapy for patients in chronic phase with a higher dose of imatinib (600 or 800 mg/d) may improve the rate of complete cytogenetic and molecular responses and the event-free and progression-free survivals with adequate tolerance. A randomized trial is currently ongoing to address whether the standard dose should be changed.

Early data from a phase III randomized, controlled clinical trial, TOPS, show that responses occurred significantly faster with an 800 mg dose of imatinib in patients with newly diagnosed CML. The TOPS study was designed to evaluate the potential benefits of an 800 mg starting dose of imatinib across all risk categories of newly diagnosed, previously untreated patients with Ph chromosome-positive (Ph+) CML. Investigators reported that significantly more patients achieved a major molecular response (MMR) with the 800 mg dose than the 400 mg dose at 3, 6, and 9 months, although the difference at 12 months was not statistically significant (54% vs 46%). This trend toward improved time to MMR in the 800 mg vs 400 mg arms was most pronounced in the subset of patients with high-risk Sokal scores (41% vs 26%). The rates of events and transformation to an accelerated or blast phase were lower for patients treated with 800 mg (1.9% and 0.9%, respectively) than for those treated with 400 mg (2.5% and 1.9%) at the first 12-month follow-up

(Cortes J et al: Blood 112: abstract 335, 2008)

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Toxicity Imatinib is well tolerated. However, several patients develop grade 1-2 adverse events, including nausea, peripheral or periorbital edema, muscle cramps, diarrhea, skin rashes, weight gain, and fatigue. These events frequently are minor and either do not require therapy or respond to adequate early intervention. Fluid retention responds to diuretics when indicated; diarrhea can be managed with loperamide or other agents; nausea usually responds to prochlorperazine, promethazine, or other agents; muscle cramps can be managed with tonic water or quinine; skin rash may be managed with antihistamines and/or corticosteroids (topical and/or systemic).

Myelosuppression is the most common grade 3-4 adverse event. Neutropenia can be seen in up to 45% of patients, thrombocytopenia in up to 25% of patients, and anemia in 10% of patients. Treatment is held for grade ≥ 3 neutropenia (neutrophil count < 109/L) or thrombocytopenia (platelet count < 50 × 109/L) and restarted when counts recover above these levels. If the recovery takes longer than 2 weeks, the dose may be reduced. Treatment interruptions and dose reductions are not usually recommended for anemia. Myelosuppression is much more likely to occur during the first 2 to 3 months of therapy and is best managed with treatment interruption and close monitoring. Hematopoietic growth factors (granulocyte colony-stimulating factor [G-CSF, filgrastim, Neupogen], oprelvekin (Neumega), and erythropoietin) have been used successfully to manage prolonged or recurrent myelosuppression, but the long-term safety of this approach needs to be assessed.

Monitoring The treatment objective has evolved from hematologic responses (hydroxyurea) to cytogenetic responses (interferon-α), to molecular responses in the imatinib era. All patients have to be evaluated with cytogenetic analysis before the start of therapy, and a baseline quantitative PCR analysis is useful. Conventional cytogenetic analysis is important at baseline and for follow-up, because it provides valuable information about the entire karyotype (ie, clonal evolution, cytogenetic abnormalities in Ph chromosome-negative cells) that cannot be obtained with FISH or PCR and has prognostic implications. A cytogenetic analysis every 3 to 6 months during the first year and every 12 to 24 months thereafter is recommended. Quantitative PCR is recommended every 3 to 6 months. It is inappropriate not to follow patients with cytogenetics and real-time PCR.

Duration of therapy At this time, the duration of therapy is unclear. A minority of patients have reached undetectable levels of disease by PCR, and few have discontinued therapy. This has usually resulted in relapse. Thus, until further evidence becomes available, patients should continue therapy indefinitely.

The higher potency of the new tyrosine kinase inhibitors compared to imatinib and the significant clinical activity seen with these agents after imatinib failure has prompted investigation of these agents as first-line therapy for patients with CML in early chronic phase. In one study, 56 patients with previously untreated CML in chronic phase were treated with nilotinib 400 mg orally twice daily. Responses occurred very rapidly, with 95% of evaluable patients achieving a complete cytogenetic response by 6 months from the start of therapy. Major molecular response had been achieved by this time in 47% of patients. Treatment was well tolerated, with minimal extramedullary toxicity, and grade 3-4 neutropenia in 11% of patients and thrombocytopenia in 9%

(Cortes J et al: Blood 112: abstract 446, 2008)

. Dasatinib was investigated in this patient population in two different schedules: 50 mg twice daily or 100 mg once daily. At 6 months from the start of therapy, 95% of patients had achieved a complete cytogenetic response, and 35% had a major molecular response. Treatment was well tolerated, with minimal grade 3 nonhematologic toxicity, and grade 3–4 thrombocytopenia in 12% and neutropenia in 21%

(Cortes J et al: Blood 112: abstract 182, 2008)

. Randomized studies comparing these strategies to standard dose imatinib are ongoing. The GIMEMA Group showed similar results with initial use of nilotinib

(Rosti G et al: Blood 112: abstract 181, 2008)

.

Imatinib failure The most frequently identified mechanism of resistance to imatinib is the development of mutations at the ABL kinase domain. Mutations are identified in 40% to 60% of patients, with the most frequent occurring in the P-loop. Not all mutations confer the same level of resistance to imatinib, and some may be overcome by increased concentrations of imatinib. The most resistant mutation is T315I. P-loop mutations have been reported to be linked to a poor prognosis, but this theory has not been confirmed in all studies, and it is probably more appropriate to consider individual mutations rather than group them by location.

Changing therapy based on molecular responses cannot be justified in most instances at the present time. Even when patients who have not achieved a 3-log reduction in transcript levels after 18 months of therapy have an inferior prognosis compared with those with at least a 3-log reduction, they still have an 86% probability of event-free survival at 7 years, and, in most instances, this only represents a loss of cytogenetic response. If the proposed alternative treatment option has any significant risk of mortality, the risk may be unnecessary. The clinical significance of the presence of mutations in patients with an adequate response is still unclear. Thus, mutations should be investigated in patients with clinical evidence of failure. In this setting, a change of therapy is indicated whether a mutation is indicated or not, but, in some instances, specific mutations may guide the selection of therapy.

The French STIM study investigated the impact of imatinib discontinuation among 69 CML patients having sustained a complete molecular remission for at least 2 years during therapy; 29 patients had not received prior imatinib. The projected probability of survival without relapse at 9 months was 53% for patients having previous interferon-exposure and 39% for those having no prior exposure. Nearly all relapses occurred within the first 6 months after discontinuation. Thus, a subset of patients may maintain a molecular remission after discontinuing imatinib, but the risk of relapse is high. The recommendation today is still to continue imatinib uninterrupted, but exploring options that may allow treatment discontinuation with minimal risk of relapse will dominate research in CML for years to come

(Mahon FX et al: Blood 112: abstract 187, 2008)

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The European LeukemiaNet has established criteria for failure that have become standard (Table 3). These criteria emphasize the response achieved and the time to such response. Patients who meet criteria for failure should be offered therapy with a secondgeneration tyrosine kinase inhibitor. For patients with suboptimal responses there are no available data indicating what the optimal management may be, although imatinib dose escalation is usually recommended.

Second-generation tyrosine kinase inhibitors A second generation of tyrosine kinase inhibitors has been developed to overcome resistance to imatinib. Two of these agents have recently gained regulatory approval (dasatinib [Sprycel] and nilotinib [Tasigna]), and others are being developed (bosutinib, SKI-606). Dasatinib is structurally unrelated to imatinib and, in contrast to it, can bind both the inactive and active configurations of BCR-ABL. In addition, dasatinib i

s a dual inhibitor that blocks Src as well as ABL and is two orders of magnitude more potent than imatinib. Both agents have been shown to inhibit both the wildtype BCR-ABL and nearly all of the clinically significant mutants of BCR-ABL, except for the T315I mutation. The results from the initial clinical trials have been impressive.

Dasatinib Dasatinib is structurally unrelated to imatinib and can bind both the inactive and active configurations of BCR-ABL. In addition, dasatinib is a dual inhibitor that blocks Src and ABL and that is two orders of magnitude more potent than is imatinib.

The initial phase II trials used a dose of 70 mg twice daily. Significant clinical activity was seen in patients in all stages of the disease after imatinib resistance or intolerance, with complete cytogenetic responses in 53% in chronic phase, 33% in accelerated phase, 27% in myeloid blast phase, and of 46% for individuals in the lymphoid blast phase. Duration of response correlates with the stage of the disease, with progression free-survival of 80% at 24 months for those in chronic phase, and 46% in accelerated phase. In contrast, the median progression-free survival was 5.6 and 3.1 months, respectively, for those in the myeloid and lymphoid blast phases. Some of the most significant adverse events include myelosuppression (grade 3-4 neutropenia and thrombocytopenia in nearly 50% each), pleural effusion, and gastrointestinal hemorrhage (particularly in the advanced stages). Alternative schedules may improve the toxicity profile. In a randomized study, dasatinib administered as 100 mg once daily was associated with significantly less myelosupression and pleural effusion when compared with 70 mg twice daily (and to 50 mg twice daily or 140 mg once daily). The response to therapy was identical, with a trend toward improved progression-free survival with use of 100 mg once daily. Dasatinib is approved for treatment of patents with CML in all phases of the disease who have experienced resistance or intolerance to imatinib. The standard dose for patients in chronic phase is 100 mg once daily; 140 mg once daily is recommended for patients in advanced stages.

Nilotinib Nilotinib was designed based on the imatinib structure and modified to improve its binding to BCR-ABL and increase its selectivity. These modifications result in an agent at least one order of magnitude more potent than imatinib against BCR-ABL.

Significant activity has been documented in patients treated after imatinib failure with nilotinib 400 mg twice daily in phase II studies. The rate of complete cytogenetic response for patients treated in chronic phase after imatinib resistance or intolerance was 42% and for those treated in accelerated phase was 19%. Responses have been durable with a sustained major cytogenetic response at 18 months in 84% of patients treated in the chronic phase. In the accelerated phase, progression-free survival is 57% at 12 months. The most significant toxicities reported have been myelosuppression (grade 3-4 neutropenia or thrombocytopenia in approximately 30%, each), and biochemical abnormalities (elevation of indirect bilirubin, lipase, and glucose) that have been usually transient and asymptomatic. There is also the potential for QTc prolongation (a class effect for all tyrosine kinase inhibitors), although less than 3% of patients have had significant prolongation, most frequently asymptomatic.

Measuring imatinib plasma levels may be a tool for managing patients receiving the drug. In the IRIS subanalysis of patients receiving imatinib as initial therapy for CML, trough plasma levels measured on day 29 of therapy were predictive of response. Those with the lowest plasma levels (< 647 ng/mL) had the lowest probability of cytogenetic and molecular response at 1 and 4 years. Patients who achieved a complete cytogenetic remission had significantly higher plasma levels than did those not responding (mean: 1,009 ng/mL vs 812 ng/mL;

P

= .01;

Larson R et al: Blood 111:4022–4028, 2008

). Similarly, in a randomized trial of 400 or 800 mg of imatinib given as initial therapy for CML in chronic phase, patients with trough plasma concentrations < 1,165 ng/mL had the lowest probability of response

(Guilhot F et al: Blood 112: abstract 447, 2008)

. This correlation emphasizes the need to optimize therapy in patients receiving imatinib.

Nilotinib is currently approved for treatment of patients in chronic or accelerated phase of the disease who have experienced resistance or intolerance to imatinib, and the standard dose is 400 mg twice daily. Nilotinib should be taken on an empty stomach as food may significantly increase the absorption.

Other agents Other investigational agents are being developed for patients who fail imatinib therapy. Bosutinib is another Src and ABL inhibitor with activity against most mutants ofBCR-ABL. Early results auggest significant activity among patients who fail imatinib therapy. Bosutinib has minimal or no activity against PDGF-R and KIT, which could lead to decreased toxicity (eg, pleural effusions and myelosuppression); however, this drug has activity against LYN and ABL and has also shown activity in patients who have failed imatinib and other tyrosine kinase inhibitors. Several agents are being developed to treat patients with the T315I mutation that is resistant to all available agents. These include homoharringtonine, MK-0457, XL-228, PHA-739358, DCC-2036, and AP24534. Early results from these trials suggest activity in some patients.

Dasatinib and nilotinib have been approved for treatment of patients with resistance or intolerance to imatinib. Other agents have also shown activity in this setting and may have unique properties. Bosutinib is an inhibitor of Bcr-Abl and Src family of kinases, but in contrast to imatinib, nilotinib and dasatinib, it has no effect against PDGFR and KIT. This increased selectivity could offer an improved toxicity profile. Bosutinib has been investigated in patients with CML who have failed other agents. Among those resistant to imatinib, 43% have achieved a major cytogenetic response after median follow up of only 7 months, with major molecular response in 42%. No pleural effusions have been reported and grade 3–4 thrombocytopenia has been reported in 21% and neutropenia in 10%

(Cortes J et al: Blood 112: abstract 1098, 2008)

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Allogeneic BMT
Allogeneic BMT is potentially curative in CML, although relapses and mortality from complications such as chronic graft-vs-host disease (GVHD) may occur many years after transplantation. Results are better for patients in the chronic phase than in either the accelerated or the blastic phase. Long-term survival rates of 50% to 80% and disease-free survival rates of 30% to 70% can be achieved in the chronic phase. The role of BMT is now changing in view of the results obtained with imatinib.

Predictors of response Early BMT within the first 1 to 3 years after diagnosis may be associated with a better outcome than is BMT performed later in the course of disease. Younger patients also have a better outcome than do older patients, with those younger than age 20 to those 30 years of age having the best prognosis. The use of the European Bone Marrow Transplant (EBMT) score helps to separate those patients who may have a better outcome from those who will not.

Conditioning regimens, including total-body irradiation (TBI), have been traditionally used, but non-TBI-containing regimens (eg, with busulfan and cyclophosphamide) have produced similar results. More recently, conditioning regimens using pharmacologic targeting of busulfan have been associated with decreased regimen-related toxicity while preserving the antileukemia effect. Also, nonmyeloablative conditioning regimens frequently containing purine analogs (mini-BMT) have been tested recently to expand the use of transplants to older patients or to those with medical conditions that preclude conventional BMT.

None of the currently available kinase inhibitors has significant activity against the T315I mutation. Homoharringtonine (omacetaxine) has been shown to have pre-clinical activity against cells carrying this mutation. In a phase II study of patients with CML resistant to imatinib who carry T315I mutation, complete hematologic responses have been reported in 85% of patients treated in chronic phase, 50% of those in accelerated phase, and 40% of patients in blast phase. Cytogenetic responses occurred in 28% of patients treated in chronic phase and 26% of those in accelerated phase. T315I transcripts became undetectable in 48% of all patients. Thus, homoharringtonine offers a good treatment option for patients with this mutation

(Cortes J et al: J Clin Oncol 27: abstract 7008, 2009)

.

GVHD The major morbidity from BMT is GVHD. T-cell depletion of the graft can reduce the incidence of this complication, but at the expense of higher relapse and graft failure rates. (For a full discussion of GVHD, see chapter 33.)

Alternatives to matched-related donors For patients who do not have a matched-related donor, matched unrelated donor transplants are reasonable alternatives. The 9-year experience from the National Marrow Donor Program in 1,432 patients reported a 3-year survival rate of 37.5%. Early transplantation results in better outcome, with patients transplanted in the chronic phase having a 3-year disease-free survival of 63%. The outcome of patients transplanted during the accelerated, blastic, or second chronic phase is inferior.

Relapse after BMT Donor leukocyte infusions are the most effective strategy to treat patients who relapse after BMT. With this strategy, 70% to 80% of patients can achieve a cytogenetic complete response; the best results are achieved when patients are treated during cytogenetic or molecular relapse. Imatinib has also been effective for patients who relapse after BMT. A complete hematologic response in more than 70% of patients, and a cytogenetic response in 58% have been reported, with the best responses obtained in patients relapsing in chronic phase.

Treatment recommendations
The long-term results of imatinib are excellent, with an overall survival of greater than 90% at 7 years. Thus, all patients in chronic phase should be offered standard-dose imatinib as initial therapy. Patients should be followed closely to determine that the expected results are met at the specified times (Table 3). If this is the case, treatment should continue uninterrupted indefinitely. For patients having a suboptimal response, a dose escalation is recommended. For patients with failure to respond to imatinib, a change in therapy to one of the second-generation tyrosine kinase inhibitors is indicated.

The role of allogeneic stem cell transplant in CML has changed, and it is considered mostly a second-line treatment option currently. For patients who fail imatinib therapy, transplant or an initial trial with a second-generation tyrosine kinase inhibitor should be considered. Adequate response at early time points is important, particularly for young patients with a transplant option. If there is no cytogenetic response at 6 months or no major cytogenetic response by 12 months, transplant should be considered.

Accelerated and blastic phases

Imatinib
Imatinib is also effective for patients with CML in transformation. Seventy-one percent of patients in accelerated phase treated with 600 mg/d of imatinib had a hematologic response. The major cytogenetic response rate was 24%, with 67% having a time to disease progression of 12 months. These results are significantly superior to those achieved using 400 mg/d, making 600 mg/d the standard dose for patients in accelerated phase. In blast phase, 52% of patients achieved a hematologic remission, and 31% achieved a sustained remission lasting at least 4 weeks with imatinib. However, the median response duration is only 10 months, even when considering only patients with sustained remission (ie, lasting at least 4 weeks). Patients with clonal evolution have a lower probability of response and a shorter survival than do patients without clonal evolution when treated with imatinib.

Nilotinib and dasatinib also have significant clinical activity in patients with advanced stage disease. Their use should be considered for patients who have failed prior therapy, including imatinib. However, responses are of shorter duration in patients in advanced stages, particularly among those in the blast phase. Combined use of these agents with other drugs (eg, standard chemotherapy) is being investigated to improve outcomes.

BMT
Compared with results in patients in the chronic phase, results with allogeneic BMT are worse in patients in the accelerated or blastic phase, with 4-year survival rates of only 10% to 30%. Patients in the accelerated phase (determined on the basis of clonal evolution only) who undergo BMT less than 1 year after diagnosis have a 4-year probability of survival of 74%. Patients in the blast phase who respond to therapy with a second-generation tyrosine kinase inhibitor should be offered a BMT in the second chronic phase if an adequate donor is available.

References:

SUGGESTED READING

Apperley JF: Part I: Mechanisms of resistance to imatinib in chronic myeloid leukaemia. Lancet Oncol 8:1018-1029, 2007.

Apperley JF: Part II: Management of resistance to imatinib in chronic myeloid leukaemia. Lancet Oncol 8:1116-1128, 2007.

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Abbreviations in this chapter
GIMEMA = Gruppo Italiano per le Malattie Ematologiche dell'Adulto; IBMTR = International Bone Marrow Transplant Registry; IRIS =International Randomized Study of Interferon and STI571; MDACC = M. D. Anderson Cancer Center; MRC = Medical Research Council; SEER = Surveillance, Epidemiology and End Results; STIM = Stop Imatinib; TOP = Tyrosine Kinase Inhibitor Optimization and Selectivity Study; WHO = World Health Organization